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4 * ~ n > <<> T (M #rt 41 Excess Lung Cancer Risk in a Synthetic Chemicals Plant by Richard J. Waxweiler,* Allan H. Smith,t Henry Falk* and Herman A. Tyroler** A ntundardized mortality ratio of 1.49 for respiratory *y*lem cancer (42 observed death* veraua 2tt.2 expected, p < 0.01) wa* obaerved among a cohort of 4M06 male* employed at a aynthetic chemical* plant *ince it* atartup in 1942. Upon review of pathologic material, the exceaa wa* found to be limited to adenocarcinoma and large cell undifferentiated lung cancer. Many of the worker* had been expoaed to vinyl chloride, a* well a* to chlorinated solvent*, polytvinyl chloride) (I'VC) dual, acrylate* and acrylonitrile. To evaluate the association between lung cancer and occupational chemical exposure*, detailed work histories for each cohort member were combined with exposure rating* for each of 19 chemical* for each job for each calendar year since 1942. A serially additive expected dose model was then constructed which compared the doses of the chemicals observed for the lung cancer cases to the doses expected based on subcohort* without lung cancer individually matched to the cases. i'VC dust appeared to be the most likely etiologic agent (p = 0.037). Time trend* of I'VC dust exposure indicated a potential i. latent period of 5-16 year* before death. Introduction data are suggestive but equivocal. Two cohort studies found no excess lung cancer risk (4-6). In six ` Our previously published (1) retrospective cohort other studies, elevated lung cancer risks were mortality study of workers exposed to vinyl chlo- found overall or among subcohorts; however, few of 11 ride monomer (VCM) at a synthetic chemicals plant these excesses were statistically significant due to demonstrated an excess risk of death front respira- moderate excess risks and/or small numbers of *' tory system cancer in addition to the already cases (7-9, 11-ld). recognized association between VCM exposure and Because of the uncertainty in the literature angiosarcoma of the liver (2-1U). Preliminary re- regarding the association between VCM exposure t view of the lung cancer cases indicated they were and lung cancer and because of the diversity of all adenocarcinomas or large cell undifferentiated occupational chemical exposures experienced by , r tumors--an unusual histologic distribution. the lung cancer cases in our previous study (1), we Although lung tumors have been induced exper- decided to evaluate our cohort further to determine ,. imentally by exposure to VCM (J), the epidemiologic whether or not lung cancer was associated with VCM or with other chemical exposures. Thus, the following research had three objectives: (1) by Industry-wide Studies Branch. Division of Surveillance, Hazard Evaluations and Field Studies. National Institute for Occupational Safety and Health, 4676 Columbia I'arkway, Cin cinnati, Ohio 45226. (Department of Community Health, Wellington Clinical School using a retrospective cohort design, to determine if our previously published excess lung cancer risk among employees exposed to VCM at this synthetic plastics plant also existed for the total plant popula of Medicine, Wellington Hospital, Wellington 2, New Zealand. t Division of Chronic Diseases, Center for Environmental Health, Centers for Disease Control, Atlanta. Georgia HO-Tl'l. `Department of Epidemiology, Selnxil of I'ulilic Health, University of North Carolina, Chapel Hill, North Carolina 27514. tion (2) by using a case-comparand study, to de termine whether an excess lung cancer risk of a particular histologic type was in force at the plant and (3) by using a serially additive expected dose model, to test whether one or more particular October 1981 159 r chemicals used at the plant were associated with either the excess risk of all or of a specific histologic type of lung cancer. Methods and Results Retrospective Cohort Study The population at risk for the retrospective co hort study consisted of the 4806 males ever em ployed at this plant from its opening in 1942 until December 31, 1973. In the absence of individual data on race, everyone was assumed to be white because the company indicated that less than 2% of the population had been nonwhite. Date of birth and detailed work histories at this plant of all jobs and dates worked by each individual were coded. By follow-up of all study members from the first date hired at the plant through December 31, 1973, it was determined that 4174 were alive and 569 had died. The 73 (1.5%) persons lost to follow-up were considered alive throughout the study. The 16 (3%) deceased persons for whom no death certificates could be located were assumed dead, cause of death unknown. A modified life table analysis (NIOSH) was used to obtain person years at risk of dying by five year age and calendar time periods. United Stales white male death rates specific for five year age and calendar intervals were used to calculate the expected deaths and standardized mortality ratios (SMR's). SMR's were tested for statistical significance using the Poisson distribution (one sided). The cohort was young; by December 31. 1973, only 30% of the cohort, if alive, would have been over 54 years of age. However, f>.n of the cohort had been hired before 1954 and thus had the oppor tunity to achieve 20 years' latency. Two separate analyses of the cohort were made. Initially, all members were considered at risk from their first date of employment at the plant. This analysis yielded 556 observed and 550 expected deaths (Table 1). Risk of death due to malignant neoplasms of the central nervous system (SMR = 209) and respiratory system (SMR = 149) were both significantly elevated. A second "over tenyear latency" analysis was carried out by beginning person-years at risk only after an individual had achieved the tenth anniversary of his first date of employment at the plant. Results similar to those in the first cohort analysis were found but with slightly higher SMR's. Respiratory system cancer had an SMR of 156 based on 39 observed cases. Because our previously published analysis (1) of just the presumably VCM-exposed workers at this plant 160 Table 1. Observed and expected death* amonjt chemical plant worker cohort. Cause (ICDA-7 Code) Observed Expected SMR All cause* All malignant neoplasms (140-205) Digestive system (150-159) Respiratory system (lfiO-lM) Central nervous system (193) Lymphatic and hematologic "(200-205) Other cancers 555* 109 24 42 9 9 25 550.2 92.5 25.6 2R.2 4.3 11.4 23.0 101 1 IS 94 149h 2<)9r 79 109 `Five persons, including three of the original 559 deaths, were not included in the cohort analysis because of missing work histories. bp < 0.01. *p < 0.05. also found an SMR of 156 after 10 years latency, these results indicate an excess lung cancer risk not solely due to VCM exposure. Case-Comparand Study The second objective of this study was to deter mine whether an excess risk existed for a particular histologic type of lung cancer. Because no historical data exist on histology-specific lung cancer inci dence or mortality rates and because histologic classification is somewhat variable between pathol ogists and over time, a case-comparand design was chosen to accomplish the second objective. Medical records and pathology reports were ob tained on all deceased members of the cohort whose death certificates mentioned cancer or respiratory dincnsc. For 45 cohort members, primary or un specified lung cancer was reported on at least one of these three records. A few persons who died after December 31, 1973, the cohort ending date, were included. Of the 45 cases, 42 were bom in Kentucky or an adjacent state. Histologic material was re quested. The worker case group consisted of the 27 of the 45 deceased individuals for whom histologic specimens were available. As a comparison group, the lung cancer cases (comparands) most closely preceding and succeed ing the chemical plant worker case in the chronolog ically ordered hospital pathology logs were selected that matched in age at diagnosis, sex, race, and county of residence. For four cases, only one matched comparand could be found. Histologic material was reviewed by a panel of pathologists unaware of the employment histories (case versus comparand status) of the deceased. The histologic type distributions, according to the Environmental Health Perspectives 21140002 4l 1 4. 1 t ; i. 11 > i> ,> <> i i I Veterans' Administration classification scheme (14), ere compared between the cases and comparands. The results of the majority opinion of the pathol ogy panel are listed in Table 2. The panel found a significantly (p < 0.05, chi-square) higher percent age of large cell undifferentiated (type 4) cancers among the worker cases than among the community comparands (30% vs. 10%). By using the SMR for respiratory system cancer of 149 in the retrospective cohort study and the observed and expected histologic distribution -of lung cancer deaths based on the case-comparand study. Table 3 demonstrates the calculation of his tology specific lung cancer SMR's (column C). If the 27 cases for which histologic specimens were avail able are considered representative of all 45 lung cancer cases, it appears the excess lung cancer risk appears limited to types 3 and 4, adenocarcinoma and large cell undifferentiated, with the greater risk due to the latter. Approximately 13.5 of the 14.8 excess lung cancers among the plant workers would be due to adenocarcinoma and large cell undifferentiated carcinoma. It appears that there is a histology-specific ex cess lung cancer risk among workers at this plant and that this differential distribution of cell types is Table 2. Cane and matched comparand histologic distribu tion*. Histologic type Veterans Ad ministration classilkation code Frequency Community Worker comparand cases cases Epidermoid Small cell undifferentiated Adenocarcinoma Large cell undifferentiated Other Total i 2 3 4 - 6 (22*4) 6 (22*4) 7 (20*4) 8 (30*4) 0 27 (100*4) 15 (30*4) 15 (30*4 ) 14 (28*4) 5 (10*4 ) 1 ( 2*4) 50 (100*4) not an artifact of the geographic region nor of the pathologist's techniques. The fact that this risk occurs for adenocarcinomas and for large cell undif ferentiated lung cancers makes it very unlikely that it is due to cigarette smoking. Serially Additive Expected Dose Model The third objective was to test whether any presumed occupational chemical exposures were associated with the excess lung cancer risk at the plant. It was decided to analyze the previously mentioned cohort data in a serially additive ex pected dose (SAED) model (JO), obtaining for each lung cancer case the observed and expected doses of each chemical, conditional on certain characteris tics. The purpose of the SAED model is to compare the observed exposure of each case in a study with the exposures of fellow workers dose to the case in year of birth, and in age at commencement of work at the company. If the total work force in the plant under study is referred to as the cohort, then each case can be thought of as belonging to a subcohort of workers with approximately the same year of birth and age at commencement of work in the plant. In each year that a case worked at the plant, his exposure can be compared with that of the other members of his subcohort who were working in that year. Company personnel compiled estimated exposures on a scale of 0 to 5 (5 being the highest exposure) for each of 19 chemicals (Table 4). Each job was as signed an ex]M).sure rank for each calendar year of the study (Table 5). These exposure data were then linked with work histories identifying the jobs each worker had in the plant and the calendar time involved. The analytical method is based on esti mating exposure dose by multiplying the exposure level by the number of days worked at that level. These "doses" are accumulated over a calendar year for a case to yield the observed dose and for Table 3. Histologic specific lung cancer risk among plant personnel. Histologic distribution Observed (A) fclxpecled KB) Histologic specific SMK C = 149 (AJB) Excess cases among thooc jmlhulugicaUy reviewed (Z))* Total Epidermoid Small cell Adenocarcinoma Large cell 100*4 22.2*4 22.2*4 25.9*4 29.0*4 98*4' 30*4 30*4 28*4 10*4 149 no no 138 441 8.9* 0.0 0.6 1.9 0.2 *D = (27 A) - (27 if x 100/149). bE = (45 A) - (45 B x 100/149). 'Specific cell types do not add up to total because of "other" type lung cancer among comparands. Total excess cases (')b 14.8* 0.9 0.9 3.2 10.3 161 boo&ffg his subcohort to yield an expected dose for each year that a case works. The methodology has pre viously been described in detail elsewhere UO). In addition to testing the total-dose hypothesis, the SAED analysis facilitates examination of the observed and expected doses for each year of exposure before death. Exposures to 19 chemicals Table 4. Exposure rating* used to cla**lfy job*. Rating Exposure 0 No exposure 1 Minimal exposure to low levels (chemical in building-- not handled, low vapor pressure and dust level, probably works on different floor) 2 Moderate exposure (works around the chemical, but exposure is minimal) 3 Works in area* where subject to occasional high excursions (normally exposure is minimal but occasional spills, leaks, or dust exposure may occur) 4 Works in areas where level is high (exposure levels in the area are frequently high; might consider that some risk is involved if chemical is very toxic) 5 Intimate contact, skin or high inhalation (such a* poly cleaners in earlier year* handling slurry) Table 5, Chemical exposure ratings specific for job identification number and calendar year for a given chemical. Chemical #1. job identifi cation number 1942 Exposure ratings 1943 1944 194!> 1940 1973 1 0002 22 2 r. r> r> fi 5 fi 3 22 1 1 00 84 4 4 4 1 1 1 were assessed; seven of the chemicals were, however, excluded from the formal analysis because so few persons were exposed to them at levels 3, 4 and 5 (Table 6). The SAED model analysis resulted in the ob served minus expected cumulative dose differences per case in Table 7. The differences for PVC dust are striking in comparison with the other expo sures. For the large cell undifferentiated cancer and adenocarcinomas combined and for large cell undifferentiated cancer by itself, the differences in exposure to PVC dust are three to four times as large as those estimated for vinylidene chloride, the Table 6. Frequency of job categories having at least one year of exposure grester than specific exposures levels.* No. at each exposure level 1 234 5 Acrylic acid Acrylamides Acrylonitrile Acetvlene Acrylates Hisphenol A Butadiene Caprvlvl chloride Chlorinated solvents Chlnroethvl vinvl ether DicthvI maleate Mercuric chloride Methanol Phenol Toluene Vinvl chloride Vinvlidono chloride Vinvl acetate PVC dust 13 4 3 0 0 14 4 4 35 25 13 00 fi 1 20 17 10 .3 1 39 .30 21 82 7 2 0 00 23 15 9 5 1 25 9 o fi 3 30 IX 7 4 4 22 fi 4 1 0 14 fi 0 0 0 15 7 h 3 3 30 21 14 22 2 1 0 <1 0 2 0 0 00 F>:*i 40 29 21 4 20 14 X 5 2 20 IX 10 50 32 19 00 9 fi *E.g., for acrylic acid, employees could have worked in 13 different job categories that had exposure levels of one or hipher in at least one calendar year between 1942 and 1973. Table 7. Observed minus expected cumulative dose difference* per lung cancer case. Chemical All lung cancers Pathologically reviewed cases Adenocarcinoma and large cell Acrvlonitrile Acetvlene Acrylates Butadiene Caprvlvl chloride Chlorinated solvents Mercuric chloride Methanol Vinvl chloride monomer Vinvlidene chloride Vinvl acetate PVC dust -052 --353 -322 -330 -547 -WW --507 -430 -1428 -341 -707 70.3 -402 -289 -251 -207 -2-5X -072 -425 -fi)8 -795 210 -4X0 244X -440 291 -K3 _4 or, -270 -150 -211 -450 2fi X04 -217 3225 I.arge cell -12X -107 -3(9 -022 -1139 749 -02 -107X 907 152.5 32X 4.520 162 Environmental Health Perspectives KKIOfrTrg r next most evident chemical. The significance levels the larger of these differences are found in Table r the total cumulative doses and also for cumula tive doses until 10 years before death. Statistical significance was observed only for exposure to PVC dust. Latency analysis for PVC dust (Kig. 1) shows a peak for the difference between observed minus expected dose during the period 5 to 1G years before death. As the diagnosis of the disease of interest becomes more narrowly defined as a patho logically homogeneous entity, the dose difference per case increases, yet the implied latent period stays constant. Discussion The first objective of this study was to determine if the excess lung cancer risk among employees exposed to VCM also existed for the total plant population, including those persons not exposed to VCM. The retrospective cohort mortality study showed that respiratory system cancers occurred approximately 50% more frequently among the em ployees of the entire plant than would have been expected based on age, sex, race, and calendar year specific United States death rates. A similar excess had been previously shown to exist among the subcohort of employees exposed to VCM (;). Thus, ' e excess lung cancer risk at the plant appeared to independent of VCM exposure unless one hy pothesized that it was due to extremely low levels of VCM that could have permeated throughout the plant. Potentially confounding variables are age, sex, calendar year, race/ethnicity, migration, urban res idence, cigarette smoking and socioeconomic status (SES). In the retrospective cohort study, age and calendar year cannot confound because they are adjusted in the results. All persons in the study are male and 98% are presumed white. White male specific rates were used for comparison to control tnose potential confounders by subject category re striction. Ethnicity and migration (both inter- and intracountry) effects are considered minimal for all three study designs because 42 of the 45 cases were born in Kentucky or an adjacent state. Urban resi dence is mainly associated with an excess of epidermoid and small cell undifferentiated lung can cer (15) rather than the histologic types of lung cancer found in excess in this study. Excess lung cancer risk is associated with low socioeconomic status (16, 17), measured either by education (rela tive risk of 1.2 for persons with fewer than eight years of school) or by occupation (relative risk of 1.3 for laborers). Since the cohort consists of a mixture of socioeconomic status levels, there is probably insignificant confounding due to SES at the plant considered as a whole. Furthermore, recent infor- Table 8. Probability value of paired /-testa of cumulative difference* between observed and expected doses for lunK cancer cases. 10 or more Total years before (all yean>)* death All cases (.V = 45) PVC dust All pathologically reviewed cases (,V - 27) PVC dust Adenocarcinoma and large cell (N = 15) PVC dust Vinylidene chloride Large cell (.V = S) PVC dust Chlorinated solvents Vinylidene chloride 0.156 O.O20b 0.037b 0.207 U.U6W 0.300 0.201 0.263 0.047b 0.001 0.333 0.177 0.435 0.322 Twelve chemicals Were tested for each lung cancer group, thus, under an assumption of independence of tests, one would expect one lest to be significant at the O.OS level. hp < 0.05. October 1981 FiouKt 1. Observed minus expected dose difference* per case among lung cancer cases for PVC dust. 163 mation indicates that these risk gradients may be partially due to smoking; patterns (/.V, 19), which would affect epidermoid and small cell undifferenti ated lung cancers. The second objective of this research was to determine whether an excess lung cancer risk of a particular histologic type existed. The case-comparand study showed that there was an excess of adenocar cinomas and large cell undifferentiated lung cancers among the cases occurring among plant employees compared to other lung cancer cases from the same community. Because the pathologists reviewed both sets of slides without knowing which were those of plant employees, it is unlikely diagnostic biases occurred. Histologic specimens were more difficult to find among the cases which died earlier and which were older on the date of death. However, community comparands were matched with the cases on age and date of diagnosis and had to have specimens available themselves; hence a biased ascertainment bv histology between cases and comparands would be unlikely. The choice of community comparands makes it unlikely that a community wide pollutant was responsible for the excess risk at the plant for types 3 and 4 lung cancer. Consequently, it can be inferred from Table 3 that the excess lung cancer risk in the cohort was limited to adenocarcinoma and large cell undifferentiated cancer. Adenocarci nomas, accounting for a minor proportion of this excess risk, have been shown to be weakly, if at all, related to cigarette smoking (14, 20-22) Large cell undifferentiated carcinoma of the lung is the only major histologic type that has appeared to be unrelated to cigarette smoking. Thus, ciga rette smoking was probably not a major confound ing variable. However, the role of smoking as a promoter or cocarcinogen cannot be ruled out. Nev ertheless, the conclusion of this phase of the inves tigation was that an excess risk occurred among plant employees for types 3 and 4 lung cancer, especially type 4. The third objective was to test whether one or more particular chemicals used at the plant were responsible for either the excess risk of all lung cancer or of the types 3 and 4 or just type 4 lung cancer. The SAED model was specifically devel oped for this objective. The major hypothesis was tested for each chemi cal in the SAED model by using the one-sided t-test of the observed minus expected cumulative doses over all years before death and ten or more years before death (Table 8). PVC dust was the only chemical that was statistically significant. These results suggest that an excess of types 3 and 4 lung cancer exists at this plant and is related to PVC, dust exposure. The suggestion of PVC dust being a lung carcin ogen is biologically plausible. Almost all PVG parti cles produced by the emulsion system, one of the systems at this plant, are in the respirable range (2.1). These particles could settle in the lungs and conceivably by themselves cause lung cancer. In fact, one case of supposedly PVC dust-induced pneu moconiosis has been found in a worker (24), and pulmonary granulomas (2!5, 26) have been induced in animals exposed to PVC dust. In a large propor tional mortality study of 4341 deaths that occurred among PVC fabricators, persons expected to be exposed to VCM and PVC dust demonstrated a slight (PMR = 117) excess lung cancer risk (27). VCM gas is easily inhaled, and possibly would be in contact with tissue only a short time before being either exhaled or absorbed into the bloodstream. However, VCM becomes entrapped in the PVC dust and can be released slowjy over time. Thus, PVC dust particles in the lung may slowly release VCM to small adjacent areas of the tissue, prolong ing the contact time of that chemical to tissue. If this latter hypothesis is true, then it begs the question of why almost all of the liver angiosarcoma cases occurred among polymer reactor cleaners who received extremely high VCM doses while the lung cancer cases occurred frequently among the less heavily exposed workers. In fact, there was no relationship between VCM and lung cancer in this analysis: yet, one would expect the lung to be the major route of entry for VCM regardless of the cancer site. REFERENCES 1. Waxweiler, R. J.. Stringer. W., Wagoner. J. K.. Jones. Falk. H.. and Cartpr. C. Neoplastic risk among workers exposed to vinvl chloride. Ann. N.Y. Acad. Sci. 271: 40-4H (1976). 2. Maltoni. C. Vinyl chloride carcinogenicity: an experimental model for carcinogenesis studies. In: Origins of Human Cancer. H. H. Hiatt. J. P. Watson, and J. A. Winslen. Eds., Cold Spring Harbor Labs., Cold Spring Harbor. N.Y., 1977. 3. Thomas. L. B., Popper. H., Berk. P. D.. Selikoff, 1.. and Falk. H. Vinyl chloride induced liver disease--from idio pathic portal hypertension (Banti's syndrome) to angio sarcomas. N. Engl. J. Med. 292: 17-22 (1975). 4. Nicholson. W. J.. Hammond. E. I).. Seidman, H.. and SelikofT, I. J. Mortality experience of a cohort of vinyl chloride-polvvinvl chloride workers. Ann. N.Y. Acad. Sci. 246: 225-230 (1975). 5. Duck. B. W,, Carter. J. T.. and Coombes. E. J. Mortalitv studv of workers in a polvvinvl chloride production plant. Lancet 2: 1197-1199 (1975). 6. Berrv, G., and Rossiter, C. E. Vinvl chloride and mortality? Lancet ii: 416-417 (1976). 164 Environmental Health I'erapoclives